Radiolabelled FAPI Radiotracers in Oncology: A Comprehensive Review of Current Diagnostic and Emerging Therapeutic Applications

TL;DR

This review explores how radiolabelled FAP inhibitors can be used for diagnosing and treating various cancers, especially those with high fibroblast activity.

Contribution

The paper provides a comprehensive synthesis of FAPI radiotracers' diagnostic and therapeutic potential, integrating molecular biology and clinical evidence.

Findings

FAPI radiotracers show high tumour-to-background contrast in cancers like pancreatic and breast cancer.

Therapeutic agents like [177Lu]Lu-FAP-2286 demonstrate safety and tumour retention in early trials.

Alpha-emitting FAPIs show strong antitumor effects in preclinical models.

Abstract

Background/Objectives: Fibroblast activation protein (FAP), which is abundantly expressed in cancer-associated fibroblasts (CAFs) across various epithelial malignancies, has emerged as a promising target for molecular imaging and radionuclide therapy. Although several reviews have addressed FAP-targeted diagnostics, a comprehensive synthesis integrating molecular biology, diagnostic performance, and early therapeutic development remains limited. This review summarises the current evidence on radionuclide-labelled FAP inhibitors (FAPIs), with particular emphasis on their diagnostic utility, emerging therapeutic applications, and the structural features that shape their biological behaviour. Methods: A structured literature search was conducted across PubMed, Scopus, and Web of Science, focusing on FAPI-based imaging and therapy. Results: Diagnostic studies consistently demonstrate high tumour-to-background contrast for [68Ga]Ga and [18F]-labelled FAPI radiotracers, particularly in tumours with prominent stromal components such as pancreatic, colorectal, breast, and head and neck cancers. FAPI PET/CT often surpasses [18F]FDG in lesion conspicuity in the brain, liver, and peritoneum. Therapeutic evidence shows encouraging tumour retention and safety profiles for agents such as [177Lu]Lu-FAP-2286 and [90Y]Y-FAPI-46, while α-emitting radiotracers (e.g., [225Ac]Ac-FAPI-04) demonstrate potent antitumor effects in preclinical models. Conclusions: Radiolabelled FAPI radiotracers hold significant potential as dual diagnostic and therapeutic agents, particularly for desmoplastic tumours with high CAF content. Nonetheless, clinical evidence remains in its early stages, and substantial questions persist regarding dosimetry, intertumoral variability in FAP expression, and optimal ligand selection for therapy. Continued development of next-generation FAPI constructs, along with well-designed prospective trials, will be crucial in defining the future role of FAPI-based theranostics in oncology.

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